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In-vitro screen of prion disease susceptibility genes using the scrapie cell assay.

Brown, CA; Schmidt, C; Poulter, M; Hummerich, H; Klöhn, PC; Jat, P; Mead, S; ... Lloyd, SE; + view all (2014) In-vitro screen of prion disease susceptibility genes using the scrapie cell assay. Hum Mol Genet , 23 (19) pp. 5102-5108. 10.1093/hmg/ddu233. Green open access

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Abstract

Prion diseases (transmissible spongiform encephalopathies) are fatal neurodegenerative diseases including Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle. While genome-wide association studies in human and quantitative trait loci mapping in mice have provided evidence for multiple susceptibility genes, few of these have been confirmed functionally. Phenotyping mouse models is generally the method of choice. However, this is not a feasible option where many novel genes, without pre-existing models, would need to be tested. We have therefore developed and applied an in-vitro screen to triage and prioritise candidate modifier genes for more detailed future studies which is faster, far more cost effective and ethical relative to mouse bioassay models. An in vitro prion bioassay, the scrapie cell assay (SCA), uses a neuroblastoma derived cell line (PK1) that is susceptible to RML prions and able to propagate prions at high levels. In this study, we have generated stable gene silencing and/or overexpressing PK1-derived cell lines to test whether perturbation of 14 candidate genes affects prion susceptibility. While no consistent differences were determined for seven genes, highly significant changes were detected for Zbtb38, Sorcs1, Stmn2, Hspa13, Fkbp9, Actr10 and Plg, suggesting that they play key roles in the fundamental processes of prion propagation or clearance. Many neurodegenerative diseases involve the accumulation of misfolded protein aggregates and "prion-like" seeding and spread has been implicated in their pathogenesis. It is therefore expected that some of these prion-modifier genes may be of wider relevance in neurodegeneration.

Type: Article
Title: In-vitro screen of prion disease susceptibility genes using the scrapie cell assay.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddu233
Publisher version: http://dx.doi.org/10.1093/hmg/ddu233
Additional information: © The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/1434067
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